3-88139639-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001350134.2(ZNF654):ā€‹c.1970A>Gā€‹(p.His657Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000089 ( 0 hom. )

Consequence

ZNF654
NM_001350134.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46
Variant links:
Genes affected
ZNF654 (HGNC:25612): (zinc finger protein 654) Predicted to enable DNA binding activity and DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]
CGGBP1 (HGNC:1888): (CGG triplet repeat binding protein 1) This gene encodes a CGG repeat-binding protein that primarily localizes to the nucleus. CGG trinucleotide repeats are implicated in many disorders as they often act as transcription- and translation-regulatory elements, can produce hairpin structures which cause DNA replication errors, and form regions prone to chromosomal breakage. CGG repeats are also targets for CpG methylation. In addition to its ability to bind CGG repeats and regulate transcription, this gene is believed to play a role in DNA damage repair and telomere protection. In vitro studies indicate this protein does not bind to methylated CpG sequences. [provided by RefSeq, Jul 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.027420849).
BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF654NM_001350134.2 linkuse as main transcriptc.1970A>G p.His657Arg missense_variant 8/9 ENST00000636215.2 NP_001337063.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF654ENST00000636215.2 linkuse as main transcriptc.1970A>G p.His657Arg missense_variant 8/95 NM_001350134.2 ENSP00000490842.1 Q8IZM8
CGGBP1ENST00000462901.5 linkuse as main transcriptc.-229+1331T>C intron_variant 1 ENSP00000418769.1 Q9UFW8
CGGBP1ENST00000467332.1 linkuse as main transcriptc.-24+1331T>C intron_variant 4 ENSP00000419459.1 C9JUJ0

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000770
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000245
AC:
6
AN:
245214
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
133182
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000337
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1460696
Hom.:
0
Cov.:
49
AF XY:
0.0000110
AC XY:
8
AN XY:
726562
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000202
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152312
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000772
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 17, 2024The c.329A>G (p.H110R) alteration is located in exon 1 (coding exon 1) of the ZNF654 gene. This alteration results from a A to G substitution at nucleotide position 329, causing the histidine (H) at amino acid position 110 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
13
DANN
Benign
0.79
DEOGEN2
Benign
0.0057
T;T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.76
T;T
M_CAP
Benign
0.0045
T
MetaRNN
Benign
0.027
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.97
.;L
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.20
.;N
REVEL
Benign
0.11
Sift
Benign
0.47
.;T
Sift4G
Benign
0.50
.;T
Polyphen
0.54
.;P
Vest4
0.069
MVP
0.043
MPC
0.26
ClinPred
0.40
T
GERP RS
5.1
Varity_R
0.078
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145744097; hg19: chr3-88188789; API